Faculty of Science and Engineering, University of Nottingham Malaysia, 43500, Semenyih, Malaysia.
Faculty of Engineering, Computing and Science, Swinburne University of Technology, 93350, Kuching, Malaysia.
Eur J Drug Metab Pharmacokinet. 2023 May;48(3):221-240. doi: 10.1007/s13318-023-00826-8. Epub 2023 Apr 24.
The major human liver drug metabolising cytochrome P450 (CYP) enzymes are downregulated during inflammation and infectious disease state, especially during coronavirus disease 2019 (COVID-19) infection. The influx of proinflammatory cytokines, known as a 'cytokine storm', during severe COVID-19 leads to the downregulation of CYPs and triggers new cytokine release, which further dampens CYP expression. Impaired drug metabolism, along with the inevitable co-administration of drugs or 'combination therapy' in patients with COVID-19 with various comorbidities, could cause drug-drug interactions, thus worsening the disease condition. Genetic variability or polymorphism in CYP2C9 across different ethnicities could contribute to COVID-19 susceptibility. A number of drugs used in patients with COVID-19 are inducers or inhibitors of, or are metabolised by, CYP2C9, and co-administration might cause pharmacokinetic and pharmacodynamic interactions. It is also worth mentioning that some of the COVID-19 drug interactions are due to altered activity of other CYPs including CYP3A4. Isoniazid/rifampin for COVID-19 and tuberculosis co-infection; lopinavir/ritonavir and cobicistat/remdesivir combination therapy; or multi-drug therapy including ivermectin, azithromycin, montelukast and acetylsalicylic acid, known as TNR4 therapy, all improved recovery in patients with COVID-19. However, a combination of CYP2C9 inducers, inhibitors or both, and plausibly different CYP isoforms could lead to treatment failure, hepatotoxicity or serious side effects including thromboembolism or bleeding, as observed in the combined use of azithromycin/warfarin. Further, herbs that are CYP2C9 inducers and inhibitors, showed anti-COVID-19 properties, and in silico predictions postulated that phytochemical compounds could inhibit SARS-CoV-2 virus particles. COVID-19 vaccines elicit immune responses that activate cytokine release, which in turn suppresses CYP expression that could be the source of compromised CYP2C9 drug metabolism and the subsequent drug-drug interaction. Future studies are recommended to determine CYP regulation in COVID-19, while recognising the involvement of CYP2C9 and possibly utilising CYP2C9 as a target gene to tackle the ever-mutating SARS-CoV-2.
主要的人类肝脏药物代谢细胞色素 P450（CYP）酶在炎症和传染病状态下下调，特别是在 2019 年冠状病毒病（COVID-19）感染期间。严重 COVID-19 期间，促炎细胞因子的涌入，称为“细胞因子风暴”，导致 CYP 下调并触发新的细胞因子释放，进一步抑制 CYP 表达。药物代谢受损，以及 COVID-19 患者与各种合并症同时使用药物或“联合治疗”，可能导致药物相互作用，从而使病情恶化。不同种族 CYP2C9 的遗传变异或多态性可能导致 COVID-19 的易感性。COVID-19 患者使用的许多药物是 CYP2C9 的诱导剂或抑制剂，或者是 CYP2C9 的代谢产物，联合使用可能会引起药代动力学和药效学相互作用。值得一提的是，一些 COVID-19 药物相互作用是由于其他 CYP 的活性改变引起的，包括 CYP3A4。异烟肼/利福平治疗 COVID-19 和结核病合并感染；洛匹那韦/利托那韦和考比司他/瑞德西韦联合治疗；或包括伊维菌素、阿奇霉素、孟鲁司特和乙酰水杨酸在内的多药治疗，称为 TNR4 治疗，都改善了 COVID-19 患者的康复。然而，CYP2C9 诱导剂、抑制剂或两者的组合，以及可能不同的 CYP 同工酶，可能导致治疗失败、肝毒性或严重副作用，包括血栓栓塞或出血，如阿奇霉素/华法林联合使用时观察到的那样。此外，CYP2C9 诱导剂和抑制剂的草药表现出抗 COVID-19 特性，计算机预测假设植物化学化合物可以抑制 SARS-CoV-2 病毒颗粒。COVID-19 疫苗引发的免疫反应会激活细胞因子释放，进而抑制 CYP 表达，这可能是 CYP2C9 药物代谢受损和随后药物相互作用的来源。建议进行未来的研究来确定 CYP 在 COVID-19 中的调节作用，同时认识到 CYP2C9 的参与，并可能将 CYP2C9 用作针对不断突变的 SARS-CoV-2 的靶基因。
